1. Field of the Invention
This invention relates to compounds having an aryl-benzimidazole structural element, in particular ones binding to nucleic acids and having anti-bacterial properties, and methods for their use.
2. Description of Related Art
A number of naturally occurring or synthetic compounds bind to double stranded nucleic acid, especially double stranded DNA (xe2x80x9cdsDNAxe2x80x9d). Some bind to the major groove, while others bind to the minor groove. Still others intercalate between adjacent base pairs. Combination binding modes are known, in which a compound has binding interactions with more than one nucleic acid site.
It has been proposed to use dsDNA binding compounds to regulate the expression of genes for medical purposes. If a disease is characterized by the overexpression or undesired expression of a gene (e.g., an oncogene), in principle the disease can be treated by suppressing wholly or partially the gene""s expression via the binding of a compound to the gene or a promoter site thereof and interfering with transcription. Infections by pathogens such as fungi, bacteria, and viruses can be treated with compounds that affect the expression of genes essential for the pathogen""s proliferation. Or, in a disease characterized by non- or under-expression of a beneficial gene, the expression of the beneficial gene can be up-regulated with a compound that binds to the binding site of a repressor.
The natural products distamycin and netropsin represent a class of DNA-binding compounds that has been studied over the years: 
Structurally, distamycin and netropsin may be viewed as heteroaromatic polyamides, having as their core structural motif N-methylpyrrole carboxamide residues. They bind to the minor groove, their crescent molecular shapes providing a conformational fit within the groove. The binding occurs with a preference for A,T rich dsDNA tracts.
A number of analogs of distamycin or netropsin have been synthesized, with the objective of enhancing or varying biological properties, increasing binding affinity to dsDNA, and/or improving specificity in base pair sequence recognition. Examples include Matsunaga et al., U.S. Pat. Nos. 5,808,087 (1998), 5,821,258 (1998), 5,852,011 (1998); JP 11-171886; and JP 11-89594.
This invention provides aryl-benzimidazole compound having the formula 
and pharmaceutically acceptable salts thereof.
Ar1 is a substituted or unsubstituted phenyl, naphthyl, 5-member heteroaromatic, 6-member heteroaromatic, or fused ring heteroaromatic group.
Subscript m is 0 or 1, while subscript n is an integer from 1 to 25, inclusive, with the proviso that if m is 0, then at least one moiety Y is a moiety M4 and n is at least 2.
Each moiety Y is independently selected from the group consisting of
(a) moieties M1 having the formula 
xe2x80x83wherein
one of X1, X2, and X3 is a ring vertex selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94NR2xe2x80x94, and the other two of X1, X2, and X3 are ring vertices selected from the group consisting of xe2x95x90Nxe2x80x94 and xe2x95x90CR1xe2x80x94;
(b) moieties M2 having the formula 
xe2x80x83wherein
x is 0 or 1 and
each R15 is independently H, OH, NH2, or F;
(c) moieties M3 having the formula 
xe2x80x83wherein each L is independently a divalent moiety separating xe2x80x94NHxe2x80x94 and xe2x80x94(Cxe2x95x90O)xe2x80x94 by 3 or 4 atoms; and
(d) moieties M4 having the formula 
xe2x80x83wherein each Ar2 is independently selected from the group consisting of 
W is N(R2)2 or OR2.
In the preceding formulae each R1 is independently H, F, Cl, Br, I, CN, OH, NO2, NH2, a substituted or unsubstituted (C1-C12)alkyl group, or a substituted or unsubstituted (C1-C12)heteroalkyl group; and each R2 is independently H, a substituted or unsubstituted (C1-C12)alkyl group, or a substituted or unsubstituted (C1-C12)heteroalkyl group.
Preferably, R1 is H, halogen (F, Cl, Br, or I), a (C1-C5)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, pentyl, and the like, a (C1-C5)alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like, hydroxy, or cyano. Preferably, each R2 is H or a (C1-C5)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, pentyl, and the like.